This invention relates to the field of pharmaceutical chemistry, and provides an advantageous process for preparing a group of benzothiophenes from dialkoxyacetophenones. The process provides the desired compounds in excellent yield on a large scale.
The preparation of benzothiophenes through a dialkoxy benzothiophene intermediate was previously described in U.S. Pat. No. 4,380,635, the disclosure of which is herein incorporated by reference, which teaches the intramolecular cyclization of .alpha.-(3-methoxyphenylthio)-4-methoxyacetophenone in the presence polyphosphoric acid (PPA). Heating the acetophenone starting material in PPA at about 85.degree. C. for about 1 hour provides an approximately 3:1 mixture of two isomers, 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene and 4-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene. However, when this reaction is conducted on a manufacturing scale, the isomeric benzothiophenes precipitate and produce a thick paste that cannot be stirred adequately in conventional manufacturing equipment.
Use of a solvent to alleviate the problem caused by a paste in a different reaction scheme has been attempted by Guy et al., Synthesis, 222 (1980). However, when this approach is applied to the instant scheme, the addition of a solvent results in incomplete cyclization of the starting acetophenone, incomplete rearrangement of 6-methoxy-3-(4-methoxyphenyl)benzo[b]thiophene, and dramatically increased reaction times.
Thus, there is a need for an improved process which employs alternate catalysts for the conversion of dialkoxyacetophenone derivatives to benzothiophenes with suitable yields and acceptable reaction times.